CA2864672C - Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme - Google Patents

Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme Download PDF

Info

Publication number: CA2864672C
Authority: CA; Canada
Prior art keywords: pyrimidin; sulfamate; pyrazolo; rac; ylamino
Prior art date: 2012-02-17
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

CA2864672A

Other languages

English (en)

French (fr)

Other versions

CA2864672A1 (en

Inventor

Roushan AFROZE

Indu T. Bharathan

Jeffrey P. Ciavarri

Paul E. Fleming

Jeffrey L. Gaulin

Mario Girard

Steven P. Langston

Francois R. Soucy

Tzu-Tshin WONG

Yingchun Ye

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Takeda Pharmaceutical Co Ltd

Original Assignee

Millennium Pharmaceuticals Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2012-02-17

Filing date

2013-02-14

Publication date

2018-01-09

2013-02-14 Application filed by Millennium Pharmaceuticals Inc filed Critical Millennium Pharmaceuticals Inc

2013-08-22 Publication of CA2864672A1 publication Critical patent/CA2864672A1/en

2018-01-09 Application granted granted Critical

2018-01-09 Publication of CA2864672C publication Critical patent/CA2864672C/en

Status Active legal-status Critical Current

2033-02-14 Anticipated expiration legal-status Critical

Links

-1 Pyrazolopyrimidinyl Chemical group 0.000 title claims description 337
108010091546 Ubiquitin-Activating Enzymes Proteins 0.000 title abstract description 50
102000018478 Ubiquitin-Activating Enzymes Human genes 0.000 title abstract description 50
239000003112 inhibitor Substances 0.000 title description 19
150000005829 chemical entities Chemical class 0.000 claims abstract description 236
150000001875 compounds Chemical class 0.000 claims abstract description 224
150000003839 salts Chemical class 0.000 claims abstract description 167
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 50
206010028980 Neoplasm Diseases 0.000 claims abstract description 40
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 271
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 152
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 150
125000005843 halogen group Chemical group 0.000 claims description 124
125000001931 aliphatic group Chemical group 0.000 claims description 118
FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 claims description 102
125000003118 aryl group Chemical group 0.000 claims description 56
125000000623 heterocyclic group Chemical group 0.000 claims description 53
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
238000000634 powder X-ray diffraction Methods 0.000 claims description 47
125000000217 alkyl group Chemical group 0.000 claims description 42
125000004438 haloalkoxy group Chemical group 0.000 claims description 38
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 36
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
125000001072 heteroaryl group Chemical group 0.000 claims description 32
201000011510 cancer Diseases 0.000 claims description 31
125000004452 carbocyclyl group Chemical group 0.000 claims description 30
125000002947 alkylene group Chemical group 0.000 claims description 23
230000005764 inhibitory process Effects 0.000 claims description 20
238000011282 treatment Methods 0.000 claims description 19
125000001309 chloro group Chemical group Cl* 0.000 claims description 18
239000003814 drug Substances 0.000 claims description 17
125000004995 haloalkylthio group Chemical group 0.000 claims description 17
125000005842 heteroatom Chemical group 0.000 claims description 17
201000010099 disease Diseases 0.000 claims description 16
239000003937 drug carrier Substances 0.000 claims description 15
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims description 14
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125000004474 heteroalkylene group Chemical group 0.000 claims description 13
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
125000001424 substituent group Chemical group 0.000 claims description 10
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
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101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 claims description 7
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201000005202 lung cancer Diseases 0.000 claims description 6
208000020816 lung neoplasm Diseases 0.000 claims description 6
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208000026310 Breast neoplasm Diseases 0.000 claims description 5
206010009944 Colon cancer Diseases 0.000 claims description 5
206010033128 Ovarian cancer Diseases 0.000 claims description 5
206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
125000001246 bromo group Chemical group Br* 0.000 claims description 5
238000002360 preparation method Methods 0.000 claims description 5
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
208000029742 colonic neoplasm Diseases 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
125000003107 substituted aryl group Chemical group 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 claims description 3
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
125000001041 indolyl group Chemical group 0.000 claims description 3
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
125000002971 oxazolyl group Chemical group 0.000 claims description 3
125000004076 pyridyl group Chemical group 0.000 claims description 3
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
125000000335 thiazolyl group Chemical group 0.000 claims description 3
125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 2
125000004145 cyclopenten-1-yl group Chemical group [H]C1=C(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
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125000000041 C6-C10 aryl group Chemical group 0.000 claims 3
201000009613 breast lymphoma Diseases 0.000 claims 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 2
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
GUAHEWCHNSONQK-SRBBEKPSSA-N 5-[7-[[(1r,2s,3r,4r)-2,3-dihydroxy-4-(sulfamoyloxymethyl)cyclopentyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]naphthalene-2-carboxylic acid Chemical compound O[C@@H]1[C@H](O)[C@@H](COS(=O)(=O)N)C[C@H]1NC1=CC=NC2=CC(C=3C4=CC=C(C=C4C=CC=3)C(O)=O)=NN12 GUAHEWCHNSONQK-SRBBEKPSSA-N 0.000 claims 1
XDXPCTFDYJMPLE-IXZQUYOESA-N [(1r,2r,3s,4r)-2,3-dihydroxy-4-[(2-pyridin-2-ylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl]methyl sulfamate Chemical compound O[C@@H]1[C@H](O)[C@@H](COS(=O)(=O)N)C[C@H]1NC1=CC=NC2=CC(C=3N=CC=CC=3)=NN12 XDXPCTFDYJMPLE-IXZQUYOESA-N 0.000 claims 1
UPUSYLJKPLQMMM-UWIFEVILSA-N [(1r,2r,3s,4r)-2,3-dihydroxy-4-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)amino]cyclopentyl]methyl sulfamate Chemical compound CC=1C=NC2=CC(C=3C=CC=CC=3)=NN2C=1N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O UPUSYLJKPLQMMM-UWIFEVILSA-N 0.000 claims 1
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
OBTLKLQNAGSDFP-VKZMIXJFSA-N methyl 5-[7-[[(1r,2s,3r,4r)-2,3-dihydroxy-4-(sulfamoyloxymethyl)cyclopentyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]naphthalene-2-carboxylate Chemical compound C=1C=CC2=CC(C(=O)OC)=CC=C2C=1C(=NN12)C=C1N=CC=C2N[C@@H]1C[C@H](COS(N)(=O)=O)[C@@H](O)[C@H]1O OBTLKLQNAGSDFP-VKZMIXJFSA-N 0.000 claims 1
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
238000000034 method Methods 0.000 abstract description 69
208000035269 cancer or benign tumor Diseases 0.000 abstract 1
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 225
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 146
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 113
238000005160 1H NMR spectroscopy Methods 0.000 description 106
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HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 74
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 58
235000002639 sodium chloride Nutrition 0.000 description 44
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
239000000243 solution Substances 0.000 description 42
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
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208000035475 disorder Diseases 0.000 description 33
102000044159 Ubiquitin Human genes 0.000 description 32
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OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 29
235000019253 formic acid Nutrition 0.000 description 29
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
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UFDGEFUTYSMTPD-UHFFFAOYSA-N 1-chloro-4-iodonaphthalene Chemical compound C1=CC=C2C(Cl)=CC=C(I)C2=C1 UFDGEFUTYSMTPD-UHFFFAOYSA-N 0.000 description 20
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
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Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Plural Heterocyclic Compounds (AREA)

CA2864672A 2012-02-17 2013-02-14 Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme Active CA2864672C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US201261600070P	2012-02-17	2012-02-17
US61/600,070		2012-02-17
PCT/US2013/026113 WO2013123169A1 (en)	2012-02-17	2013-02-14	Pyrazolopyrimidinyl inhibitors of ubiquitin-activating enzyme

Publications (2)

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CA2864672A1 CA2864672A1 (en)	2013-08-22
CA2864672C true CA2864672C (en)	2018-01-09

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US (4)	US9290500B2 (es)
EP (3)	EP2814791A4 (es)
JP (1)	JP6122877B2 (es)
KR (1)	KR20140123104A (es)
CN (1)	CN104136399B (es)
AR (1)	AR092797A1 (es)
BR (1)	BR112014020365B1 (es)
CA (1)	CA2864672C (es)
CL (1)	CL2014002181A1 (es)
CO (1)	CO7071135A2 (es)
CR (1)	CR20140380A (es)
DO (1)	DOP2014000187A (es)
EA (1)	EA035020B1 (es)
EC (1)	ECSP14019113A (es)
ES (1)	ES2739150T3 (es)
GE (1)	GEP201706687B (es)
HK (1)	HK1201817A1 (es)
IL (1)	IL234016A0 (es)
MA (1)	MA35932B1 (es)
MX (1)	MX352963B (es)
NZ (1)	NZ628969A (es)
PE (1)	PE20142244A1 (es)
PH (1)	PH12014501832A1 (es)
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CL2014002181A1 (es)	2014-12-12
UA116534C2 (uk)	2018-04-10
EA035020B1 (ru)	2020-04-17
HK1201817A1 (en)	2015-09-11
CN104136399B (zh)	2018-08-07
EP3173413B1 (en)	2019-05-01
CR20140380A (es)	2014-10-28
EA201400831A1 (ru)	2014-12-30
DOP2014000187A (es)	2014-10-15
JP2015508775A (ja)	2015-03-23
GEP201706687B (en)	2017-06-26
EP3536692B1 (en)	2021-04-07
IL234016A0 (en)	2014-09-30
TW201345909A (zh)	2013-11-16
US20140088096A9 (en)	2014-03-27
AR092797A1 (es)	2015-05-06
PE20142244A1 (es)	2015-01-07
US9290500B2 (en)	2016-03-22
TN2014000351A1 (en)	2015-12-21
US9796725B2 (en)	2017-10-24
BR112014020365A2 (pt)	2020-12-22
US20170369499A1 (en)	2017-12-28
US20160244455A1 (en)	2016-08-25
SG10201606581RA (en)	2016-09-29
UY34629A (es)	2013-09-02
EP2814791A4 (en)	2015-08-19
MX2014009944A (es)	2014-11-10
JP6122877B2 (ja)	2017-04-26
EP2814791A1 (en)	2014-12-24
PH12014501832A1 (en)	2014-11-17
US20130217682A1 (en)	2013-08-22
MX352963B (es)	2017-12-15
US20170217968A1 (en)	2017-08-03
TWI593688B (zh)	2017-08-01
ECSP14019113A (es)	2015-09-30
BR112014020365B1 (pt)	2023-02-23
MA35932B1 (fr)	2014-12-01
CO7071135A2 (es)	2014-09-30
EP3173413A1 (en)	2017-05-31
NZ628969A (en)	2017-03-31
WO2013123169A1 (en)	2013-08-22
ES2739150T3 (es)	2020-01-29
CN104136399A (zh)	2014-11-05
US10202389B2 (en)	2019-02-12
SG11201404757WA (en)	2014-09-26
EP3536692A1 (en)	2019-09-11
ZA201406103B (en)	2017-11-29
CA2864672A1 (en)	2013-08-22
KR20140123104A (ko)	2014-10-21
US9663525B2 (en)	2017-05-30

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